Editorial: ART: Does 'singleton' really equal success?

November 1, 2005

IVF- and ICSI conceived singleton fetuses are at higher risk of birth defects, IUGR, PTD, and perinatal mortality.

Approximately 1% of US infants are conceived through assisted reproductive technology (ART), according to the CDC's 2005 survey of these techniques.2 In 2002, 428 participating centers reported performing 115,392 ART procedures, resulting in 45,751 infants. Forty-seven percent of the ART-conceived infants-or 21,597-were singletons. While much has been published about the enormous public health and personal burden of ART-derived multifetal pregnancies, little attention has been paid to the short- and long-term outcomes of ART-conceived singleton gestations. But this state of benign neglect is rapidly changing.

Recent evidence suggests that IVF- and ICSI-conceived singleton fetuses are at higher risk of birth defects, intrauterine growth restriction (IUGR), PTD, and perinatal mortality than their spontaneously conceived brothers and sisters. The link between ART and anomalies was brought to the public's attention with publication of Hansen and colleagues' landmark paper.3 In that 2002 report, the adjusted odds ratios (OR) for congenital anomalies among IVF- and ICSI-conceived singleton infants were 2.2 (95% CI: 1.4–3.4) and 2.1 (1.2–4.0), respectively. The major abnormalities the investigators observed were cardiac, genitourinary, facial, and extremity defects. A 2005 meta-analysis of 51 studies, which used strict methodologic controls, showed an OR of 1.31 (1.17–1.45) for anomalies among ART-conceived singletons, and the increased risk was associated with both traditional IVF and ICSI.4 The authors concluded that ART was associated with a 30% to 40% increase in birth defects.

Preliminary data also indicate that ART procedures may be associated with higher rates of rare disorders of DNA methylation (that is, imprinting disorders) such as Beckwith-Wiedemann and Angelman syndromes.8 The former is associated with omphalocele, macroglossia, and gigantism, while the latter is associated with severe mental retardation.

Indeed, the evidence of a link between ART and congenital anomalies is sufficiently convincing that the focus of the discussion is now on the mechanism. Are ART-associated anomalies caused by the procedure itself or the underlying infertility? Consider these potential culprits:

(1) effects of IVF culture medium and conditions on meiosis, mitosis, embryonic cell proliferation and differentiation, DNA methylation and histone acetylation;
(2) effects of oocyte and embryo manipulation on embryonic apoptosis and abnormal compaction;
(3) potential harmful effects from superphysiologic levels of gonadotropins and ovarian steroids used for, or induced by, ovulation induction regimens; and
(4) underlying infertility problem (such as the insulin-resistant/glucose intolerant and hyperandrogen state linked to polycystic ovarian syndrome or the often increased oocyte age of ART-requiring mothers).